The ex vitro study of malignant cell populations has established some general principles by which clinical treatment protocols are developed. These principles have established differences between malignant and normal cell populations and have been employed in the treatment of malignant disease. There have been attempts to exploit these differences, both in pre-clinical and clinical studies, to obtain total tumor cell kills and improved cure rates.
One of the major obstacles in achieving this goal has been the difficulty in minimizing normal tissue toxicity while increasing tumor cell kill (therapeutic index). Thus, some treatment strategies employ an empirical approach in the treatment of malignant disease. In particular, the time of delivery and dose of cytotoxic agents can be guided more by the response and toxicity to normal tissue than by the effects on the malignant cell population.
Unfortunately, this approach may not provide accurate information on the changes during treatment of a malignant cell population. Making this information available may allow clinicians to exploit the differences between malignant and normal cells, and hence improve the treatment procedures.
There have been a number of attempts to study changes that occur within a cell population. However, these attempts have not shown the ability to monitor the changes on a real time basis. Indeed, these methods typically provide information at one point in time and most are designed to provide information on one particular function or parameter. In addition, most of the conventional methods can be expensive as well as time consuming. This can be problematic for patients undergoing extended treatment periods typical of radiation and chemotherapy, especially when it is desirable to follow changes both during an active treatment and subsequent to the active treatment.
In addition, tumors may have periods in which they are more susceptible to treatment by radiation or drug therapy. Providing a monitoring system which can continuously or semi-continuously monitor and potentially identify such a susceptible condition could provide increases in tumor destruction rates.
Numerous tumor specific antigens (TSA) have been identified and antibodies specific for a number of these TSA's are known. For example, it has been demonstrated that sigma-2 receptors found on the surface of cells of the 9L rat brain tumor cell line, the mouse mammary adenocarcinoma lines 66 (diploid) and 67 (aneuploid), and the MCF-7 human breast tumor cell line may be markers of tumor cell proliferation. See Mach R H et al., Sigma 2 receptors as potential biomarkers of proliferation in breast cancer. Cancer Res 1997 Jan. 1; 57(1):156-61; Al-Nabulsi I et al., Effect of ploidy, recruitment, environmental factors, and tamoxifen treatment on the expression of sigma-2 receptors in proliferating and quiescent tumour cells. Br J Cancer 1999 November; 81(6):925-33. Such markers may be amenable to detection by non-invasive imaging procedures. Accordingly, ligands that selectively bind sigma-2 receptors may be used to assess the proliferative status of tumors, although in vivo techniques utilizing such ligands have heretofore not been known. Although the field of tumor-specific treatment is still relatively unsettled, various researchers have proposed several potentially important techniques useful in such treatment. For example, the ex vitro detection of biomolecules can be useful in predicting the timing for advantageous treatment of tumors. Many of these techniques use a “hybridization event” to alter the physical or chemical properties associated with the biomolecules. The biomolecules having the altered property can be detected, for example, by optical or chemical means.
One known technique for the detection of biomolecules, called Enzyme-Linked Immunosorbent Assay (ELISA), involves the detection of binding between a biomolecule and an enzyme-labeled antibody specific for the biomolecule. Other methods of detecting biomolecules utilize immunofluorescence, involving the use of a fluorescently labeled antibody to indicate the presence of the biomolecule. The in vivo use of these techniques may involve an invasive introduction of a sensor into the in vivo site to be analyzed. Moreover, these techniques may not be reliable if the surface where the sensor and the tissue interact is not clean. In particular, in vivo use can cause a sensor to become “bio-fouled” over time such that the operational properties of the sensor may change. In particular, proteins may begin to develop on the sensor within minutes of insertion of the sensor into the tissue, which may cause the sensor to operate improperly. In view of the foregoing, there remains a need for circuits, compositions of matter, and methods which can be used to, inter alia, detect biomolecular concentrations in vivo.